Breast cancer is the most frequently diagnosed malignancy in women and the leading cause of cancer mortality in women worldwide. The global incidence of breast cancer is estimated to reach 5 million women in the next decade [Parkin, D M and Fernandez L M, Use of statistics to assess the global burden of breast cancer. Breast Journal. 2006; (12, Suppl 1):S70-80; World Health Statistics. 2008, World Health Organization.] In 2007, breast cancer accounted for approximately 540,000 deaths worldwide [World Health Organization Fact Sheet No. 297. 2008; available from WHO web site.]
The erbB (erythroblastic leukemia viral oncogene homolog) family of TKIs (Tyrosine Kinase Inhibitors) consists of 4 members: erbB-1 (EGFR [epidermal growth factor receptor]), erbB-2 (HER-2, neu), erbB-3 (HER-3) and erbB-4 (HER-4). The erbB family of receptors is involved in cell proliferation, tumorigenesis, and metastasis and is abnormally expressed in multiple tumor types. HER2-positive breast cancers, i.e., those which test positive for the protein called human EGFR, are associated with Erb-2-protein overexpression or erbB-2 gene amplification in breast cancer tumors has been associated with more aggressive clinical disease and poorer prognosis [Slamon D, Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science. 1987 (235):177-182].
Trastuzumab, a humanized monoclonal antibody that selectively binds to the human erbB-2 receptor, improves the prognosis of women with erbB-2-positive breast cancer. In patients with erbB-2 overexpressing metastatic breast cancer, trastuzumab in combination with chemotherapy improves tumor regression, extends time to tumor progression and prolongs median survival over chemotherapy alone resulting in its approval as first-line treatment in the metastatic setting. [Ligibel J A and Winer E P, Trastuzumab/chemotherapy combinations in metastatic breast cancer. Seminars in Oncology. 2002; 29(3 Suppl 11): 38-43]. Herceptin (trastuzumab) [Package insert, Genentech (2008)]. Trastuzumab has also been approved for use in the adjuvant setting in combination with other drugs for treatment of erbB-2 overexpressing node positive or node negative (estrogen receptor/progesterone receptor [ER/PgR] negative) metastatic breast cancer. Thus, trastuzumab has been used as part of a treatment regimen consisting of (a) doxorubicin, cyclophosphamide, and either paclitaxel or docetaxel, (b) a regimen with docetaxel and carboplatin, and (c) as a single agent following multi-modality anthracycline based therapy.
The current standard of care after diagnosis with HER+ breast cancer is surgery, followed by adjuvant treatment for a year. Standard adjuvant treatment is some combination of chemotherapy, radiation, hormonal therapy for ER/PR positive disease and trastuzumab. Despite completion of adjuvant therapy, patients with early stage breast cancer remain at risk for relapse. Published reports of trastuzumab therapy show disease-free-survival rates ranging from 80.6% [Smith I, et al. 2-year follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer: a randomized controlled trial. Lancet. 2007; 369:29-36] at three years to 85.9% to 82% at four years [Perez E A, et al., Updated results of the combined analysis of NCCTG N9831 and NSABP B-31 adjuvant chemotherapy with/without trastuzumab in patients with HER2-positive breast cancer. Journal of Clinical Oncology. ASCO Annual Meeting Proceedings. 2007; 25(18S): 512 and Slamon D, et al., Phase III trial comparing AC-T with AC-TH and with TCH in the adjuvant treatment of HER2 positive early breast cancer patients: second interim efficacy analysis. Presentation by Slamon D. SABCC 2006].
HKI-272 (neratinib) has been described for the treatment of neoplasms [U.S. Pat. No. 6,288,082]. Neratinib is a potent irreversible pan erbB inhibitor. Neratinib is an orally available small molecule that inhibits erbB-1, erbB-2 and erbB-4 at the intracellular tyrosine kinase domains, a mechanism of action that is different from trastuzumab. Neratinib reduces erbB-1 and erbB-2 autophosphorylation, downstream signaling, and the growth of erbB-1 and erbB-2 dependent cell lines. Preclinical data suggest that neratinib will have antitumor activity in erbB-1- and/or erbB 2-expressing carcinoma cell lines, with cellular IC50<100 nM [Rabindran S K, et al. Antitumor activity of HKI-272, an orally active, irreversible inhibitor of the HER-2 tyrosine kinase. Cancer Research. 2004; 64(11):3958-65].
What are needed are drugs and regimens which improve patient survival rates and/or drugs and regimens which decrease recurrence of breast cancer following completion of primary and adjuvant treatment.